Response-adaptive designs for continuous outcomes

In this paper, we propose two new response-adaptive designs to use in a trial comparing treatments with continuous outcomes. Both designs assign more subjects to the better treatment on average. The new designs are compared with existing procedures and the equal allocation. The power of the treatment comparison is assessed.     

Variance-penalized response-adaptive randomization with mismeasurement

We consider response-adaptive design of clinical trials under a variance-penalized criterion in the presence of mismeasurement. An explicit expression for the variance-penalized criterion with misclassified dichotomous responses is derived for response-adaptive designs and some properties are discussed. A new target proportion of treatment allocation is proposed under the criterion and related simulation results are presented.     

An optimal allocation for response-adaptive designs

A new allocation proportion is derived by using differential equation methods for response-adaptive designs. This new allocation is compared with the balanced and the Neyman allocations and the optimal allocation proposed by Rosenberger, Stallard, Ivanova, Harper and Ricks (RSIHR) from an ethical point of view and statistical power performance. The new allocation has the ethical advantages of allocating more than 50% of patients to the better treatment. It also allocates higher proportion of patients to the better treatment than the RSIHR optimal allocation for success probabilities larger than 0.5. The statistical power under the proposed allocation is compared with these under the balanced, the Neyman and Rosenberger's optimal allocations through simulation. The simulation results indicate that the statistical power under the proposed allocation proportion is similar as to those under the balanced, the Neyman and the RSIHR allocations.     

Sequential estimation for covariate-adjusted response-adaptive designs

In clinical trials, a covariate-adjusted response-adaptive (CARA) design allows a subject newly entering a trial a better chance of being allocated to a superior treatment regimen based on cumulative information from previous subjects, and adjusts the allocation according to individual covariate information. Since this design allocates subjects sequentially, it is natural to apply a sequential method for estimating the treatment effect in order to make the data analysis more efficient. In this paper, we study the sequential estimation of treatment effect for a general CARA design. A stopping criterion is proposed such that the estimates satisfy a prescribed precision when the sampling is stopped. The properties of estimates and stopping time are obtained under the proposed stopping rule. In addition, we show that the asymptotic properties of the allocation function, under the proposed stopping rule, are the same as those obtained in the non-sequential/fixed sample size counterpart. We then illustrate the performance of the proposed procedure with some simulation results using logistic models. The properties, such as the coverage probability of treatment effect, correct allocation proportion and average sample size, for diverse combinations of initial sample sizes and tuning parameters in the utility function are discussed.     

Intermediate Monitoring,Sample Size Reassessment,and Multi-Treatment Optimal Response-Adaptive Designs for Phase III Clinical Trials with More Than One Constraint

Optimal response-adaptive designs in Phase III clinical trial set up are becoming more and more current interest. In the present article, an optimal response-adaptive design is introduced for more than two treatments at hand. We minimize an objective function subject to more than one inequality constraints. For this purpose, we propose an extensive computer search algorithm. The proposed procedure is illustrated with extensive numerical computation and simulations. Some real data set is used to illustrate the proposed methodology.     

Multi-arm response-adaptive designs for circular responses

A multi-arm response-adaptive allocation design is developed for circular treatment outcomes. Several exact and asymptotic properties of the design are studied. Stage-wise treatment selection procedures based on the proposed response-adaptive design are also suggested to exclude the worse performing treatment(s) at earlier stages. Detailed simulation study is carried out to evaluate the proposed selection procedures. The applicability of the proposed methodologies is illustrated through a real clinical trial data on cataract surgery.     

Response-adaptive randomization for survival trials: the parametric approach

Summary.  Few references deal with response-adaptive randomization procedures for survival outcomes and those that do either dichotomize the outcomes or use a non-parametric approach. In this paper, the optimal allocation approach and a parametric response-adaptive randomization procedure are used under exponential and Weibull distributions. The optimal allocation proportions are derived for both distributions and the doubly adaptive biased coin design is applied to target the optimal allocations. The asymptotic variance of the procedure is obtained for the exponential distribution. The effect of intrinsic delay of survival outcomes is treated. These findings are based on rigorous theory but are also verified by simulation. It is shown that using a doubly adaptive biased coin design to target the optimal allocation proportion results in more patients being randomized to the better performing treatment without loss of power. We illustrate our procedure by redesigning a clinical trial.     

Adaptive Crossover Design for Normal Responses

In a response-adaptive design, we review and update the trial on the basis of outcomes in order to achive a specific goal. In clinical trials our goal is to allocate a larger number of patients to the better treatment. In the present paper, we use a response adaptive design in a two-treatment two-period crossover trial where the treatment responses are continuous. We provide probability measures to choose between the possible treatment combinations AA, AB, BA, or BB. The goal is to use the better treatment combination a larger number of times. We calculate the allocation proportions to the possible treatment combinations and their standard errors. We also derive some asymptotic results and provide solutions on related inferential problems. The proposed procedure is compared with a possible competitor. Finally, we use a data set to illustrate the applicability of our proposed design.     

Some Restricted randomization rules in sequential designs

This paper presents a new class of designs (Big Stick Designs) for sequentially assigning experimental units to treatments, when only the time covariate is considered. By prescribing the degree of imbalance which the experimenters can tolerate, complete randomization is used as long as the imbalance of the treatment allocation does not exceed the prescribed value. Once it reaches the value, a deterministic assignment is made to lower the imbalance. Such designs can be easily implemented with no programming and little personnel support. They compare favorably with the Biased Coin Designs, the Permuted Black Designs, and the Urn Designs, as far as the accidental bias and selection bias are concerned. Generalizations of these designs are considered to achieve various purposes, e.g., avoidance of deterministic assignments, early balance, etc.     

Randomization tests in recursive response-adaptive randomization procedures

In a randomized clinical trial, response-adaptive randomization procedures use the information gathered, including the previous patients' responses, to allocate the next patient. In this setting, we consider randomization-based inference. We provide an algorithm to obtain exact p-values for statistical tests that compare two treatments with dichotomous responses. This algorithm can be applied to a family of response adaptive randomization procedures which share the following property: the distribution of the allocation rule depends only on the imbalance between treatments and on the imbalance between successes for treatments 1 and 2 in the previous step. This family includes some outstanding response adaptive randomization procedures. We study a randomization test to contrast the null hypothesis of equivalence of treatments and we show that this test has a similar performance to that of its parametric counterpart. Besides, we study the effect of a covariate in the inferential process. First, we obtain a parametric test, constructed assuming a logit model which relates responses to treatments and covariate levels, and we give conditions that guarantee its asymptotic normality. Finally, we show that the randomization test, which is free of model specification, performs as well as the parametric test that takes the covariate into account.     

Longitudinal covariate-adjusted response-adaptive randomized designs

Clinical trials often involve longitudinal data set which has two important characteristics: repeated and correlated measurements and time-varying covariates. In this paper, we propose a general framework of longitudinal covariate-adjusted response-adaptive (LCARA) randomization procedures. We study their properties under widely satisfied conditions. This design skews the allocation probabilities which depend on both patients' first observed covariates and sequentially estimated parameters based on the accrued longitudinal responses and covariates. The asymptotic properties of estimators for the unknown parameters and allocation proportions are established. The special case of binary treatment and continuous responses is studied in detail. Simulation studies and an analysis of the National Cooperative Gallstone Study (NCGS) data are carried out to illustrate the advantages of the proposed LCARA randomization procedure.     

Asymptotic normality of maximum likelihood estimators from multiparameter response-driven designs

Estimation and inference for dependent trials are important issues in response-adaptive allocation designs; maximum likelihood estimation is one route of interest. We present three noval response-driven designs and derive their maximum likelihood estimators. We also provide convenient regularity conditions that ensure the maximum likelihood estimator from a multiparameter stochastic process exists and is asymptotically multivariate normal. While these conditions may not be the most general, they are easily verified for our applications.     

A signature enrichment design with Bayesian adaptive randomization

Clinical trials in the era of precision cancer medicine aim to identify and validate biomarker signatures which can guide the assignment of individually optimal treatments to patients. In this article, we propose a group sequential randomized phase II design, which updates the biomarker signature as the trial goes on, utilizes enrichment strategies for patient selection, and uses Bayesian response-adaptive randomization for treatment assignment. To evaluate the performance of the new design, in addition to the commonly considered criteria of Type I error and power, we propose four new criteria measuring the benefits and losses for individuals both inside and outside of the clinical trial. Compared with designs with equal randomization, the proposed design gives trial participants a better chance to receive their personalized optimal treatments and thus results in a higher response rate on the trial. This design increases the chance to discover a successful new drug by an adaptive enrichment strategy, i.e. identification and selective enrollment of a subset of patients who are sensitive to the experimental therapies. Simulation studies demonstrate these advantages of the proposed design. It is illustrated by an example based on an actual clinical trial in non-small-cell lung cancer.     

Construction and analysis of edge designs from skew-symmetric supplementary difference sets

The purpose of screening experiments is to identify the dominant variables from a set of many potentially active variables which may affect some characteristic y. Edge designs were recently introduced in the literature and are constructed by using conferences matrices and were proved to be robust. We introduce a new class of edge designs which are constructed from skew-symmetric supplementary difference sets. These designs are particularly useful since they can be applied for experiments with an even number of factors and they may exist for orders where conference matrices do not exist. Using this methodology, examples of new edge designs for 6, 14, 22, 26, 38, 42, 46, 58, and 62 factors are constructed. Of special interest are the new edge designs for studying 22 and 58 factors because edge designs with these parameters have not been constructed in the literature since conference matrices of the corresponding order do not exist. The suggested new edge designs achieve the same model-robustness as the traditional edge designs. We also suggest the use of a mirror edge method as a test for the linearity of the true underlying model. We give the details of the methodology and provide some illustrating examples for this new approach. We also show that the new designs have good D-efficiencies when applied to first order models.     

Optimal and lead-in adaptive allocation for binary outcomes: A comparison of Bayesian methods

We compare posterior and predictive estimators and probabilities in response-adaptive randomization designs for two- and three-group clinical trials with binary outcomes. Adaptation based upon posterior estimates are discussed, as are two predictive probability algorithms: one using the traditional definition, the other using a skeptical distribution. Optimal and natural lead-in designs are covered. Simulation studies show that efficacy comparisons lead to more adaptation than center comparisons, though at some power loss, skeptically predictive efficacy comparisons and natural lead-in approaches lead to less adaptation but offer reduced allocation variability. Though nuanced, these results help clarify the power-adaptation trade-off in adaptive randomization.     

m-Associate PBIB designs using Youden-m squares

In this paper, we have proposed a type of arrangement that we call Youden-m square and is similar to the usual Youden square but generates PBIB designs instead of BIB designs when its columns are taken as blocks. We have also discussed its construction methodologies, introduced two new m-associate class association schemes, and also constructed some series of Youden-m square type PBIB designs.     

An urn model to construct an efficient test procedure for response adaptive designs

We study the statistical performance of different tests for comparing the mean effect of two treatments. Given a reference classical test \({\mathcal {T}}_0\), we determine which sample size and proportion allocation guarantee to a test \({\mathcal {T}}\), based on response-adaptive design, to be better than \({\mathcal {T}}_0\), in terms of (a) higher power and (b) fewer subjects assigned to the inferior treatment. The adoption of a response-adaptive design to implement the random allocation procedure is necessary to ensure that both (a) and (b) are satisfied. In particular, we propose to use a Modified Randomly Reinforced Urn design and we show how to perform the model parameters selection for the purpose of this paper. Then, the opportunity of relaxing some assumptions on treatment response distributions is presented. Results of simulation studies on the test performance are reported and a real case study is analyzed.     

A numerical study for comparing two response-adaptive designs for continuous treatment effects

We study two sequential, response-adaptive randomized designs for clinical trials; one has been proposed in Bandyopadhyay and Biswas (Biometrika 88: 409–419, 2001) and in Biswas and Basu (Sankhya Ser B 63:27–42, 2001), the other stems from the randomly reinforced urn introduced and studied in Muliere et al. (J Stat Plan Inference 136:1853–1874, 2006a). Both designs can be used in clinical trials where the response from each patient is a continuous variable. Comparison is conducted through numerical studies and along a new guideline for the evaluation of a response-adaptive design.     

Cumulative cohort design for dose-finding

We introduce a new design for dose-finding in the context of toxicity studies for which it is assumed that toxicity increases with dose. The goal is to identify the maximum tolerated dose, which is taken to be the dose associated with a prespecified “target” toxicity rate. The decision to decrease, increase or repeat a dose for the next subject depends on how far an estimated toxicity rate at the current dose is from the target. The size of the window within which the current dose will be repeated is obtained based on the theory of Markov chains as applied to group up-and-down designs. But whereas the treatment allocation rule in Markovian group up-and-down designs is only based on information from the current cohort of subjects, the treatment allocation rule for the proposed design is based on the cumulative information at the current dose. We then consider an extension of this new design for clinical trials in which the subject's outcome is not known immediately. The new design is compared to the continual reassessment method.     

A theoretical analysis of the power of biased coin designs

Outlining some recently obtained results of Hu and Rosenberger [2003. Optimality, variability, power: evaluating response-adaptive randomization procedures for treatment comparisons. J. Amer. Statist. Assoc. 98, 671–678] and Chen [2006. The power of Efron's biased coin design. J. Statist. Plann. Inference 136, 1824–1835] on the relationship between sequential randomized designs and the power of the usual statistical procedures for testing the equivalence of two competing treatments, the aim of this paper is to provide theoretical proofs of the numerical results of Chen [2006. The power of Efron's biased coin design. J. Statist. Plann. Inference 136, 1824–1835]. Furthermore, we prove that the Adjustable Biased Coin Design [Baldi Antognini A., Giovagnoli, A., 2004. A new “biased coin design” for the sequential allocation of two treatments. J. Roy. Statist. Soc. Ser. C 53, 651–664] is uniformly more powerful than the other “coin” designs proposed in the literature for any sample size.